laxagol powder for oral solution, pl 17507 0091 powder for oral solution is a laxative for the...

MHRA PAR; LAXAGOL POWDER FOR ORAL SOLUTION, PL 17507/0091 1

Public Assessment Report

Decentralised Procedure

LAXAGOL powder for oral solution

PL 17507/0091

UK/H/1446/01/DC

Auden Mckenzie (Pharma Division) Ltd.


Lay summary

The Medicines and Healthcare products Regulatory Agency (MHRA) granted Auden Mckenzie (Pharma Division) Ltd. a Marketing Authorisation (licence) for the medicinal product LAXAGOL powder for oral solution (Product Licence number: PL 17507/0091). This medicine is available from pharmacies without prescription. LAXAGOL powder for oral solution is a laxative for the treatment of constipation. LAXAGOL helps you to have a normal bowel movement even if you have been constipated for a long time. LAXAGOL also works when there is a build up of hard faeces in your bowel which may be the result of long-term constipation (called faecal impaction). LAXAGOL contains macrogol 3350 which makes your faeces softer and easier to pass, giving you relief from constipation. The electrolytes help to maintain your body’s normal levels of sodium, potassium and water while you are being treated for constipation. The data submitted in support of this application for LAXAGOL powder for oral solution raised no clinically significant safety concerns and it was therefore judged that the benefits of using this product outweigh the risks; hence a Marketing Authorisation has been granted.


TABLE OF CONTENTS

Module 1: Information about decentralised procedure Page 4 Module 2: Summary of Product Characteristics Page 5 Module 3: Product Information Leaflets Page 10 Module 4: Labelling Page 14 Module 5: Scientific Discussion Page 17 1 Introduction 2 Quality aspects 3 Non-clinical aspects 4 Clinical aspects 5 Overall conclusions


Module 1

Information about decentralised procedure

Name of the product in the Reference Member State


Type of application (Eudratrack details) Level 1 Abridged Level 2 Initial Level 3 10.1 Level 4 Chemical substance Level 5 Pharmacy

Name of the active substance (INN)

Macrogol 3350 Sodium Chloride Sodium Hydrogen Carbonate

Potassium Chloride Pharmacotherapeutic classification (ATC code)

Osmotically acting laxatives A06A D65

Pharmaceutical form and strength

Powder for solution for oral consumption, single-dose sachet, 13.8 g

Reference numbers for the Mutual Recognition Procedure

UK/H/1446/01/DC

Reference Member State

United Kingdom

Member States concerned

Ireland

Date of start of the procedure 5 December 2008

End date of decentralised procedure 6 August 2009

Marketing Authorisation Number PL 17507/0091

Name and address of the authorisation holder

Auden Mckenzie (Pharma Division) Ltd. Mckenzie House Bury Street Ruislip Middlesex HA4 7TL UK


Module 2

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT


2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each sachet of LAXAGOL contains the following active ingredients:

Macrogol 3350 13.125 g

Sodium chloride 350.7 mg

Sodium bicarbonate (Sodium hydrogen carbonate) 178.5 mg

Potassium chloride 46.6 mg

The content of electrolyte ions per sachet when made up to 125 ml of solution is as follows:

Sodium 65 mmol/l

Chloride 53 mmol/l

Potassium 5.4 mmol/l

Bicarbonate (Hydrogen carbonate) 17 mmol/l

For a full list of excipients, see Section 6.1

3 PHARMACEUTICAL FORM

Powder for oral solution. Single-dose sachet containing a free flowing white powder.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

For the treatment of chronic constipation. LAXAGOL is also effective in resolving faecal impaction, defined as refractory constipation with faecal loading of the rectum and/or colon.

4.2 Posology and method of administration

Chronic constipation A course of treatment for constipation with LAXAGOL does not normally exceed 2 weeks, although this can be repeated if required. As for all laxatives, prolonged use is not usually recommended. Extended use may be necessary in the care of patients with severe chronic or resistant constipation, secondary to multiple sclerosis or Parkinson's Disease, or induced by regular constipating medication in particular opioids and antimuscarinics.


Adults, adolescents and the elderly: 1 –3 sachets daily in divided doses, according to individual response. For extended use, the dose can be adjusted down to 1 or 2 sachets daily. Children below 12 years old: Not recommended. Faecal impaction A course of treatment for faecal impaction with LAXAGOL does not normally exceed 3 days. Adults, adolescents and the elderly: 8 sachets daily, all of which should be consumed within a 6 hour period. Children below 12 years old: Not recommended. Patients with impaired cardiovascular function: For the treatment of faecal impaction the dose should be divided so that no more than 2 sachets are taken in any one hour. Patients with renal insufficiency: No dosage change is necessary for the treatment of constipation or faecal impaction. Administration Each sachet should be dissolved in 125 ml water. For use in faecal impaction 8 sachets may be dissolved in 1 litre of water.

4.3 Contraindications

Intestinal perforation or obstruction due to structural or functional disorder of the gut wall, ileus, severe inflammatory conditions of the intestinal tract, such as Crohn's disease and ulcerative colitis and toxic megacolon. Hypersensitivity to the active ingredients or to any of the excipients.

4.4 Special warnings and precautions for use

Diagnosis of impaction/faecal loading of the rectum should be confirmed by physical or radiological examination of the abdomen and rectum. Mild adverse drug reactions are possible as indicated in Section 4.8. If patients develop any symptoms indicating shifts of fluids/electrolytes (e.g. oedema, shortness of breath, increasing fatigue, dehydration, cardiac failure) LAXAGOL should be stopped immediately and electrolytes measured and any abnormality should be treated appropriately. LAXAGOL contains 0.68mmol (26mg) of potassium per sachet. This should be taken into consideration if more than one sachet is taken daily and for those patients that have reduced kidney function, or are on a controlled potassium diet. LAXAGOL contains 8.13mmol (187mg) of sodium per sachet. This should be taken into consideration for patients on a controlled sodium diet. The lemon flavouring used in LAXAGOL may contain sulphites. This may rarely cause severe hypersensitivity reactions and bronchospasm.


4.5 Interaction with other medicinal products and other forms of interaction No clinical interactions with other medicinal products have been reported. Macrogol raises the solubility of medicinal products that are soluble in alcohol and relatively insoluble in water. There is therefore a theoretical possibility that the absorption of such medicinal products could be transiently reduced. Therefore, other medicines should not be taken orally for one hour before and one hour after taking LAXAGOL.

4.6 Pregnancy and lactation

There is no experience of the use of LAXAGOL during pregnancy and lactation and it should only be used if considered essential by the physician.

4.7 Effects on ability to drive and use machines

LAXAGOL has no influence on the ability to drive and use machines.

4.8 Undesirable effects Immune System Disorders: Allergic reactions are possible. Gastro-intestinal Disorders: Potential gastro-intestinal effects that may occur include abdominal distension and pain, borborygmi and nausea. Mild diarrhoea may also occur, but normally resolves after dose reduction.

4.9 Overdose

Severe pain or distension can be treated by nasogastric aspiration. Extensive fluid loss by diarrhoea or vomiting may require correction of electrolyte disturbances.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Osmotically acting laxatives. ATC code: A06A D65 Macrogol 3350 acts by virtue of its osmotic action in the gut, which induces a laxative effect. Macrogol 3350 increases the stool volume, which triggers colon motility via neuromuscular pathways. The physiological consequence is an improved propulsive colonic transportation of the softened stools and a facilitation of the defaecation. Electrolytes combined with macrogol 3350 are exchanged across the intestinal barrier (mucosa) with serum electrolytes and excreted in faecal water without net gain or loss of sodium, potassium and water. For the indication of faecal impaction controlled comparative studies have not been performed with other treatments (e.g. enemas). In a non-comparative study in 27 adult patients, the listed combination of active substances cleared the faecal impaction in 12/27 (44%) after 1 day's treatment; 23/27 (85%) after 2 days' treatment and 24/27 (89%) at the end of 3 days. Clinical studies using the listed active substances in the treatment of chronic constipation have shown that the dose needed to produce normal formed stools tends to reduce over time. Many


patients respond to between 1 and 2 sachets a day, but this dose should be adjusted depending on individual response.

5.2 Pharmacokinetic properties

Macrogol 3350 is unchanged along the gut. It is virtually unabsorbed from the gastro-intestinal tract. Any macrogol 3350 that is absorbed is excreted via the urine.

5.3 Preclinical safety data

Preclinical studies provide evidence that macrogol 3350 has no significant systemic toxicity potential, although no tests of its effects on reproduction or genotoxicity have been conducted. There are no long-term animal toxicity or carcinogenicity studies involving macrogol 3350, although there are toxicity studies using high levels of orally administered high molecular macrogols that provide evidence of safety at the recommended therapeutic dose.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Acesulfame potassium(E950) Lemon flavour (Lemon flavour contains the following constituents: nature-identical flavouring substances, flavouring preparations, natural flavouring substances, maltodextrin and starch modified).

6.2 Incompatibilities

Not applicable.

6.3 Shelf life 2 years. Reconstituted solution: 6 hours.

6.4 Special precautions for storage

Sachet: Do not store above 25°C. Reconstituted solution: Store at 2 - 8°C (in a refrigerator and covered).

6.5 Nature and contents of container

Sachet: laminate consisting of four layers: low density polyethylene, aluminium, low density polyethylene and paper. Pack sizes: boxes of 2, 8, 20, 30, 50 or 100 sachets. Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused solution should be discarded within 6 hours.

7 MARKETING AUTHORISATION HOLDER

Auden Mckenzie (Pharma Division) Ltd. Mckenzie House Bury Street Ruislip


Middlesex HA4 7TL UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 17507/0091

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 25/09/2009 10 DATE OF REVISION OF THE TEXT

25/09/2009


Module 3

Product Information Leaflet


Module 4

Labelling

Label:


Carton:


Module 5

Scientific discussion during initial procedure

RECOMMENDATION Based on the review of the data on quality, safety and efficacy, the Reference Member State (RMS) considers that the application for LAXAGOL powder for oral solution in the treatment of chronic constipation and in resolving faecal impaction is approvable. EXECUTIVE SUMMARY ABOUT THE PRODUCT Macrogol 3350 acts by virtue of its osmotic action in the gut, which induces a laxative effect. Macrogol 3350 increases the stool volume, which triggers colon motility via neuromuscular pathways. The physiological consequence is an improved propulsive colonic transportation of the softened stools and a facilitation of the defaecation. Electrolytes combined with macrogol 3350 are exchanged across the intestinal barrier (mucosa) with serum electrolytes and excreted in faecal water without net gain or loss of sodium, potassium and water. GENERAL COMMENTS ON THE SUBMITTED DOSSIER This is a Decentralised Procedure with the United Kingdom acting as the Reference Member State. The application is submitted under article 10.1 of Directive 2001/83/EC, as amended, cross-referring to the UK product Movicol (PL 00322/0070) licensed to Norgine Limited since 18 December 1995. With UK as the Reference Member State in this Decentralized Procedure, Auden Mckenzie (Pharma Division) Ltd. is applying for a Marketing Authorisation for LAXAGOL powder for oral solution in Ireland. GENERAL COMMENTS ON COMPLIANCE WITH GMP, GLP, GCP AND AGREED ETHICAL PRINCIPLES. The RMS has been assured that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture and assembly of this product. For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites. For manufacturing sites located outside the Community, the RMS has accepted a copy of the current GMP certificate of satisfactory inspection issued by the inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those non-Community sites. The RMS has been reassured that the submitted studies have been carried out in accordance with GCP, and agreed ethical principles.


SCIENTIFIC OVERVIEW AND DISCUSSION QUALITY ASPECTS Drug substance The chemical-pharmaceutical documentation and Expert Report in relation to LAXAGOL powder for oral solution are of sufficient quality in view of the present European regulatory requirements. The active substances, Macrogol 3350, sodium chloride, sodium bicarbonate (sodium hydrogen carbonate) and potassium chloride which are the subjects of Ph Eur monographs and are controlled by current certificates of suitability. The drug substance specifications for the drug substances are acceptable. Stability studies have been performed with the drug substance. No significant changes in any parameters were observed. An adequate re-test period has been defined based on conducted stability studies. Drug Product The development of the product has been described, the choice of excipients is justified and their functions explained. The product specifications cover appropriate parameters for this dosage form. Validations of the analytical methods have been presented. The batch analysis results show that the finished products meet the specifications proposed. The conditions used in the stability studies are according to the ICH stability guideline. The control tests and specifications for drug product are adequately drawn up. The proposed shelf-life of 2 years is acceptable. NON CLINICAL ASPECTS The pharmacodynamic, pharmacokinetic and toxicological properties of the drug substances are well known. As Macrogol 3350, sodium chloride, sodium bicarbonate and potassium chloride are all well known active substances, no further new non-clinical data are required and the applicant has provided none. An overview based on the literature is thus appropriate. The non-clinical overview has been written by a qualified medical doctor with extensive drug safety and clinical research experience. The overview, dated October 2008, refers to four references from the published literature dated 1986 to 2007. The toxicological properties of the drug substances are well known. The nonclinical overview is acceptable. CLINICAL ASPECTS Biowaiver A bioequivalence study has not been performed. The Note for Guidance CPMP/EWP/QWP/1401/98 states that if the product is an aqueous solution at the time of administration, and contains an active substance in the same concentration as an oral solution currently approved, no bioequivalence study is required providing the ingredients contained in it do not affect gastrointestinal transit, absorption or in-vivo stability of the active. Laxagol, once reconstituted, contains the same active ingredients in the same concentration as Movicol, the only difference being flavouring which does not affect transit time, absorption or in-vivo stability of the active. With regard to solubility, although Laxagol has to be dissolved in water before administration, the resulting solution has been shown to be completely soluble (the accepted definition of highly water soluble being when the amount contained in the highest dose strength of an immediate release product is dissolved in 250ml of each of three buffers in the range 1 – 8 at 37°C). Solubility of Laxagol in 250ml of 0.1M HCl (pH1), pH 4 and pH 6.8 buffers has been tested


for each of the actives contained in one sachet and each dissolved completely with minimal stirring; it can therefore be considered highly water soluble. In addition, a study was undertaken to show that the Laxagol product dissolved at the same speed as the originator, Movicol. A sample of Movicol was dispensed into 125ml of potable water. This was mixed for 10 seconds and then left to settle for 10 seconds. A few visible lumps remained after this time so the solution was mixed for a further 10 seconds and allowed to settle for 10 seconds. After this time, it was noted that the solution was clear and colourless with no visible lumps remaining. A similar study was conducted using the developed product. It was found that this product dissolved in exactly the same way as the brand. It can be confirmed that complete dissolution of both products occurs in less than 1 minute. Therefore, the absence of a bio-equivalence study is justified. Pharmacodynamics No new data have been submitted and none are required for this generic application. Clinical efficacy No new data have been submitted and none are required for this generic application. Clinical safety No new data have been submitted and none are required for this generic application. Pharmacovigilance system The RMS considers that the pharmacovigilance system as described by the applicant fulfils the requirements and provides adequate evidence that the applicant has the services of a qualified person responsible for pharmacovigilance and has the necessary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country. Risk Management Plan LAXAGOL powder for oral solution is a generic product. As with the reference medicinal product, no special important risks or potential risks have been identified which require additional risk minimization activities other than the global pharmacovigilance system. Product literature All product literature (SPC, PIL and labelling) is satisfactory. The package leaflet was submitted to the MHRA along with results of consultations with target patient groups ("user testing"), in accordance with Article 59 of Council Directive 2001/83/EC. The results indicate that the package leaflet is well-structured and organised, easy to understand and written in a comprehensive manner. The test shows that the patients/users are able to act upon the information that it contains. BENEFIT RISK ASSESSMENT The application contains an adequate review of published clinical data and, for reasons discussed above, the demonstration of bioequivalence compared to the originator Movicol is unnecessary. Approval is recommended.

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